NSAIDs are an important therapeutic class of drugs typically used to suppress pain and inflammation. Drugs belonging to this class typically possess one or more of the following four major activities: analgesic (provide relief of pain by a mechanism other than reduction of inflammation), antipyretic (ability to lower elevated body temperature), anti-inflammatory (ability to reduce inflammation), and uricosuric (ability to promote excretion of uric acid, e.g., for treating gout); recently, certain NSAIDs have also emerged as effective cancer chemotherapeutic and chemopreventive agents (Mehanna, A. S., Am. J. of Pharmaceutical Education 2003: 67(2), Article 63; Koki, A. T., et al., Expert Opin Investig Drugs, 1999, 8:1623-38). The mechanism of action of NSAIDs involves reproduction of prostaglandin synthesis by inhibition of the cyclooxygenase (COX) enzyme through competitive antagonism for arachidonic acid binding to COX. Structurally, NSAIDs possess both a lipophilic and an acidic moiety, which enables them to mimic the natural substrate chemistry of COX binding. Structural classes of NSAID compounds include the following: (i) the salicylates (e.g., aspirin belongs to this category), (ii) aniline derivaties (such as acetaminophen), (iii) pyrazole derivatives such as Felsol®, (iv) N-arylanthranilic acid derivatives (also known as fenamates), (v) indole-3-acetic acid derivatives such as Indocin®, (vi) other arylacetic and arylpropionic acid derivatives such as Naprosyn®, Advil®, Toradol® and (vii) oxicams such as Feldene®.
Although these drugs are commonly administered for pain management, their side effects can range from minor to severe. Associated side effects include stomach upset, headache, drowsiness, easy bruising, asthma, high blood pressure and/or fluid retention. The most serious risks associated with NSAID treatment are gastrointestinal, such as the occurrence of gastrointestinal mucosal injury. In severe cases, serious gastrointestinal toxicity, such as bleeding, peptic ulceration, perforation and gastrointestinal bleeding (which can sometimes be severe and occasionally fatal) can occur, with or without warning symptoms, during NSAID therapy. In fact, gastrointestinal side effects cause an estimated 16,000 deaths and 107,000 cases of hospitalization each year in the United States (Fries, J., et al., 1998, Clinical Significance and Potential of Selective Cox-2 Inhibitors, William Harvey Press (London), 557-573). In the case of ketorolac, a drug frequently used for relief of moderate to severe post-operative pain, its recommended course of administration is limited to no longer than 5 days, due to the high likelihood of severe gastric-related side-effects associated with longer term administration and/or high doses of this drug. This is unfortunate, since clinical studies have indicated that ketorolac, a non-narcotic analgesic, possesses a single dose efficacy greater than that of morphine for postoperative pain, making it a highly desirable painkiller of choice. Thus, ketorolac, along with other members of the NSAID class of molecules, could benefit from alternative drug forms or delivery systems that are capable of prolonging the course of dosing and/or ameliorating some of the severe side effects associated with its administration.
Although alternative delivery systems have been explored to date, none have proven to be extremely effective in solving the drawbacks associated with administration of NSAIDs such as ketorolac. Such approaches have included passive transdermal delivery, iontophoretic administration, as well as nasal formulations.
For example, in an exploration of the passive transdermal delivery of ketorolac through human skin, the in vitro flux of ketorolac through cadaver skin was found to decrease substantially upon lamination of a pressure sensitive adhesive onto a microporous membrane (Roy, S. D., Manoukian, E., J. Pharm. Sci. 1995, 84(10): 1190-6). Iontophoretic-facilitated transdermal transport of ketorolac through rat skin has also been investigated (Tiwari, S., Udupa, Int. J. Pharmaceutics, 260 (1), July 2003:930103). While iontophoresis resulted in an improvement of ketorolac drug flux in comparison to diffusion-based transport, the most effective improvement was observed in the case of an extremely cumbersome trimodal regime: pre-treatment with D-limonene in ethanol in combination with ultrasound, followed by iontophoretic-facilitated delivery. In fact, in order to achieve a significant degree of drug transport, the authors had to rely upon both physical (iontophoresis and phonophoresis) and chemical (chemical penetration enhancer) methods. Moreover, both iontophoretic administration and the use of certain chemical penetration enhancers such as d-limonene, are often accompanied by skin irritation and rash—making this administration regime unattractive for widespread patient use. Moreover, complicated administration regimes such as the foregoing are frequently accompanied by extremely low patient compliance. Various types of nasal formulations of ketorolac have also been investigated including spray and powder formulations (Quadir, M. et al., Drug. Deliv. 2000 7(4):223-9). Drawbacks associated with such nasal formulations included limited dissolution of ketorolac into the mucous layer, resulting in reduced absorption into the bloodstream, and limited drug release from a polymer-matrix based powder formulation.
Thus, there is a need in the art for improved NSAID compositions, e.g., for localized or non-localized delivery, preferably allowing less frequent patient dosing and a reduced occurrence of severe associated side effects. This invention meets these needs.